The present invention relates to diterpene derivatives and anti-inflammatory analgesic agents comprising the same. More specifically, the present invention relates to diterpene derivatives prepared from the components which are extracted from Acanthopanax Koreanum and represented by Chemical Formula 1: 
wherein, R1 and R2 individually represent hydrogen or hydroxy, or they form a double bond in the cycle, R3 represents vinyl, hydroxyethyl, methoxyethyl, acetyloxyethyl, methoxymethoxyethyl, methoxyethoxymethoxyethyl, methoxyiminoethyl or isoxazolinyl group, R4 represents hydroxymethyl, carboxyl, carboxymethyl, carboxyvinyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxybutadienyl, carboxyallyl, carboxyhomoallyl, carbamoyl, methylcarbamoyl, hydroxycarbamoyl, carbazoyl, N-pipsylcarbamoylmethyl, N-pipsylcarbamoylethyl, N-pipsylcarbamoylbutadienyl or N-methanesulfonylcarbamoylethyl group; and anti-inflammatory analgesic agents comprising the same.
Acanthopanax Koreanum is a special product which grows spontaneously in Cheju-do in the Republic of Korea. It is a deciduous shrub belong to the family of Japanese angelica tree, and taking-out of the tree from Cheju-do is restricted. The bark of the tree and the bark of the root have been known to have effective analgesic action on pain of bones and sinews from ancient times in the field of Chinese medicines. Among the people, wine was made from the bark or root-bark of Acanthopanax Koreanum, and the win has been used for treatment of neuralgia, paralysis, hypertension and rheumatism.
Recently, the present inventors found the fact that (xe2x88x92)-pimara-9(11),15-diene-4-carboxylic acid among the diterpene components extracted from root-bark and bark of Acanthopanax Koreanum, and novel derivatives synthesized therefrom inhibits the stage where arachidonic acid is converted to PGE2, an inflammation mediator, thereby having excellent anti-inflammatory action, and the discovery was filed as a patent application (Korean Patent No. 112194).
The present inventors have continuously performed intensive studies in order to discover an excellent inhibitor against production of PGE2(prostagladin E2), and as a result, could additionally develop a compound having more excellent anti-inflammatory action, and complete the present invention.
The object of the present invention is to provide diterpene derivatives represented by Chemical Formula 1.
Another object of the present invention is to provide an anti-inflammatory analgesic agent comprising the diterpene derivative represented by Chemical Formula 1.
The present invention relates to diterpene derivatives represented by Chemical Formula 1 and anti-inflammatory analgesic agents comprising the same. 
wherein, R1, R2, R3 and R4 are the same as defined previously.
The compound of Chemical Formula 1 is prepared from the components extracted from Acanthopanax Koreanum, and the process for preparation is described in detail here-in-below:
First, root-bark and bark of Acanthopanax Koreanum is cut into pieces and the pieces are heat-extracted with alcohol in a water bath, and the extract is filtered. After concentrating the combined filtrate of the alcohol extract, water is added, and the mixture is extracted with diethyl ether. The ether extract is concentrated to dryness, and the residue is fractioned by silica gel column chromatography using a mixture of ethyl acetate and hexane as an eluent, to give (xe2x88x92)-pimara-9(11),15-diene-4-carboxylic acid (R4=COOH) of Chemical Formula 2, the main component of the fractions. In the description of compounds of Chemical Formulas 2 to 48 below, the definitions of R1 to R4 in the parentheses are described in order to show how the substituents R1 to R4 of Chemical Formulas 2 to 48 are characteristically altered as compared to Chemical Formula 1.
The compound of Chemical Formula 2 is subjected to chemical reactions shown in Reaction Schemes 1 to 7, to form various derivatives. 
As shown in Reaction Scheme 1, the natural diterpene (R4=COOH) of Chemical Formula 2 is reduced, and then oxidized, using tetrapropylammonium perruthenate, PDC, PCC or Swern oxidation to give a compound (R4=CHO) of Chemical Formula 3. The aldehyde group of the compound of Chemical Formula 3 thus obtained is subjected to Wittig reaction using triethylphosphono acetate anion in tetrahydrofuran to obtain a double bond in the compound of Chemical Formula 6. The double bond of the conjugated ester is reduced by magnesium in methanol, or directly hydrolyzed with lithium hydroxide to obtain a compound of Chemical Formula 7 (R4=CH2CH2COOH) or that of Chemical Formula 8 (R4=CHCHCOOH). The compound of Chemical Formula 4 (R4=CHCHOCH3) obtained from Wittig reaction using methoxymethyl phosphorane is hydrolyzed by p-toluenesulfonic acid in acetone to give an aldehyde, which is oxidized by silver oxide in water and ethanol to give a compound of Chemical Formula 5 (R4=CH2COOH).
Carbonyl derivatives of the present invention can be prepared according to Reaction Scheme 2 or 3 shown below. 
As shown in Reaction Scheme 2, the natural diterpene of Chemical Formula 2 (R4=COOH) is directly reacted with oxalyl chloride or thionyl chloride in benzene to give a compound of Chemical Formula 9 (R4=COCl), which is reacted with aqueous ammonia or aqueous solution of methyl amine in ethyl acetate, with hydroxylamine hydrochloride in benzene, or with hdyrazine monohydrate in dry ether, to give a compound of Chemical Formula 10 (R4=CONH2), a compound of Chemical Formula 11 (R4=CONHCH3), a compound of Chemical Formula 12(R4=CONHNH2, carbazoyl), and a compound of Chemical Formula 13 (R4=CONHOH), respectively.
Similarly, the acid chloride group of the compound of Chemical Formula 9 is reacted with trimethylsilyl ethanol in pyridine to give a compound of Chemical Formula 14 (R4=COOCH2CH2TMS) wherein the carboxylic group is protected, which is then reacted with two equivalents of borane-methyl sulfide in tetrahydrofuran and deprotected with tetrabutylammonium fluoride in dimethylformamide to give a compound of Chemical Formula 15 (R1=OH, R2=H, R3=CH2CH2OH, R4=CO2H). Otherwise, the compound of Chemical Formula 14 wherein the carboxylic group is protected (R4=COOCH2CH2TMS) is subjected to additional cyclization using nitrile oxide, which was obtained from N-chlorosuccinimide and acetaldoxime, in tetrahydrofuran, and then deprotected with tetrabutylammonium fluoride to give a compound of Chemical Formula 16 (R1, R2=double bond, R4=isoxazolinyl). 
As shown in Reaction Scheme 3 above, the natural diterpene of Chemical Formula 2 (R4=COOH) is reacted with n-butyllithium in tetrahydrofuran to obtain a carboxylate salt, which is reduced by one equivalent of borane-methyl sulfide complex (BH3xe2x80x94SMe2) to give an objective compound of Chemical Formula 17 (R3=CH2CH2OH), without giving any effect on the carboxylic group. The compound of Chemical Formula 17 thus obtained is reduced on contact to give a compound of Chemical Formula 18 (R1=H2, R2H, R3=CH2CH2OH). 
As shown in Reaction Scheme 4 above, the aldehyde group of the compound of Chemical Formula 19 (R4=CH2CHO), which was obtained by hydrolzying the compound of Chemical Formula 4 as in Reaction Scheme 1, is subjected to Wittig reaction in toluene to obtain a double bond. The conjugated ester is directly hydrolyzed by lithium hydroxide, or reduced by magnesium in methanol and hydrolyzed, to provide a compound of Chemical formula 21 (R4=CH2CHCHCOOH) or a compound of Chemical Formula 23 (R4=CH2CH2CH2COOH). 
As shown in Reaction Scheme 5 above, the conjugated ester group of the compound of Chemical Formula 6 (R4=CHCHCO2Et), which was obtained in Reaction Scheme 2, is reduced and then oxidized with tetrapropylammonium perruthenate to provide a compound of Chemical Formula 24 (R4=CHCHCHO). The aldehyde is subjected to Wittig reaction with triethyl phosphonoacetate anion in tetrahydrofuran to give a diene, which is hydrolyzed with lithium hydroxide to provide a compound of Chemical Formula 25(R4=CHCHCHCHCO2H).
Otherwise, the conjugated ester group of the compound of Chemical Formula 6 (R4=CHCHCO2Et) is reacted with magnesium in methanol to reduce the double bond and with diisobutylaluminium hydride to reduce the ester group, and then oxidized with tetrapropylammonium perruthenate to give a compound of Chemical formula 27 (R4=CH2CH2CHO).
The aldehyde group of the compound of Chemical Formula 27 thus obtained is subjected to Wittig reaction using triethyl phosphonoacetate anion in tetrahydrofuran to obtain a double bond, and the double bond of the conjugated ester is directly hydrolyzed with lithium hydroxide, or reduced with magnesium in methanol and hydrolyzed to provide a compound of Chemical Formula 29 (R4=CH2CH2CHCHCOOH, carboxyhomoallyl) or a compound of Chemical Formula 31 (R4=CH2CH2CH2CH2COOH).
The pipsylcarbamoyl derivatives of the present invention can be prepared as shown in Reaction Scheme 6 below 
The carboxylic group of the compound of Chemical Formula 5, 7 or 25 is directly reacted with oxalyl chloride or thionyl chloride in benzene, to give an acid chloride, which is then reacted with pipsylamide anion or methanesulfonamide anion obtained by treating pipsylamide or methansulfonamide with sodium hydride in tetrahydrofuran, to give a compound of Chemical Formula 32 (R4=CH2CONHSO2PhI, pipsylcarbamoylmethyl), a compound of Chemical Formula 33 (R4=CH2CH2CONHSO2PhI, pipsylcarbamoylethyl), a compound of Chemical Formula 34 (R4=CH2CH2CONHSO2CH3, methanesulfonylcarbamoylethyl) and a compound of Chemical Formula 35 (R4=CHCHCHCHCONHSO2PhI, pipsylcarbamoylbutadienyl), respectively. 
As shown in Reaction Scheme 7 above, the hydroxy group of the compound of Chemical Formula 36 (R3=CH2CH2OH, R4=CO2CH2CH2TMS), which was obtained by reacting the ester of Chemical Formula 14 obtained in Reaction Scheme 3 with 1 equivalent of borane-methyl sulfide, is treated with sodium hydride-iodomethane, acetic anhydride, or methoxymethyl chloride, or methoxyethoxymethyl chloride and deprotected with tetrabutylammonium fluoride in dimethylsulfoxide, to provide a compound of Chemical Formula 41 (R3=CH2CH2OCH3), a compound of Chemical Formula 42 (R3=CH2CH2OAc), a compound of Chemical Formula 43 (R3=CH2CH2OCH2OCH3) and a compound of Chemical Formula 44 (R3=CH2CH2OCH2OCH2CH2OCH3), respectively.
Meanwhile, the hydroxy group of the compound of Chemical Formula 36 is oxidized with tetrapropylammonium perruthenate to provide a compound of Chemical Formula 45 (R3=CH2CHO), which is condensed with methoxylamine, and deprotected with tetrabutylammonium fluoride in dimethylsulfoxide to give a compound of Chemical Formula 47 (R3=CH2CHNOCH3).
The dose of the compound represented by Chemical Formula 1 is 0.01 to 1000 mg for an adult per one day as an defined as an anti-inflammatory analgesic agent, and the dose may be conventionally varied depending on age and body weight of the patient as well as the condition of symptoms.
The anti-inflammatory analgesic agent of the present invention may be formulated in proper forms which are suitable for oral administration or parenteral administration, according to the conventional processes for preparing formulations. In case of oral administration, the anti-inflammatory analgesic agent of the present invention may be prepared in the form of a tablet, capsule, solution, syrup, suspension, or the like, while in case of parenteral administration it may be prepared in the form of intraperitoneal, subcutaneous, intramuscular, or transcutaneous injection.
The present invention is described in more detail with reference to the Examples. It should be noted that the scope of the present invention is not restricted in those Examples.